SETBP1SET binding protein 1

Score

Autism Reports / Total Reports

Rare Variants / Common Variants

31 / 0

Aliases

SETBP1, SEB

Associated Syndromes

Schinzel-Giedion syndrome

Genetic Category

Rare Single Gene Mutation, Syndromic

Chromosome Band

18q12.3

Associated Disorders

ID, ASD

Relevance to Autism

A de novo LoF variant (frameshift) was identified in a simplex ASD case from the Simons Simplex Collection (O'Roak et al., 2012). More recently, eight loss-of-function variants, three of which were de novo in origin, were identified in patients from DD/ID cohorts; social difficulties and/or other behavioral difficulties were observed in four of these patients (Coe et al., 2014).

Molecular Function

The protein encoded by this gene has been shown to bind the SET nuclear oncogene, which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome (SGMFS) [MIM:269150], a disorder characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia.

SFARI Gene score

Suggestive Evidence

Score Delta: Increased from 3 to 4.5 + acc2

criteria met

Suggestive Evidence

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018

3

4.5 + acc2

Increased from 3 to 4.5 + acc2

Description

3

4/1/2017

3

3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

10/1/2016

3

3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2016

3

3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2015

3

3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Reports Added

10/1/2014

3

Increased from to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Krishnan Probability Score

Score 0.49774287812693

Ranking 2338/25841 scored genes

[Show Scoring Methodology]

Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.

ExAC Score

Score 0.99900292938104

Ranking 1066/18225 scored genes

[Show Scoring Methodology]

The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt

Sanders TADA Score

Score 0.89128171866151

Ranking 5613/18665 scored genes

[Show Scoring Methodology]

The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).

Larsen Cumulative Evidence Score

Score 24

Ranking 84/461 scored genes

[Show Scoring Methodology]

Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.